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Int J Biochem Cell Biol. 2014 Apr;49:42-52. doi: 10.1016/j.biocel.2014.01.003. Epub 2014 Jan 15.

All-trans retinoic acid (ATRA) induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity.

Author information

  • 1Cell Immunity in Cancer, Inflammation and infection Group, Biomedical Research Center of Aragon (CIBA), Nanoscience Institute of Aragon (INA), Aragon I+D Foundation (ARAID), IIS Aragon/University of Zaragoza, Zaragoza 50009, Spain.
  • 2INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France.
  • 3Institut de Recherche en Cancérologie de Montpellier INSERM U896, Université Montpellier 1, CRLC Val d'Aurelle Paul Lamarque, Montpellier F-34298, France.
  • 4Apoptosis, Immunity and Cancer Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, University of Zaragoza, Zaragoza 50009, Spain.
  • 5Progenika Biopharma SA, Parque Tecnológico Bizkaia 504, 48160 Derio, Bizkaia, Spain.
  • 6Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, 1919 route de Mende, 34293 Montpellier cedex 5, France. Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France. Université Montpellier 1, 5 Bd Henry IV, 34967 Montpellier Cedex 2, France.
  • 7INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France; Institut de Recherche en Biothérapie (IRB), CHU Montpellier, Montpellier 34295, France. Electronic address: martin.villalba@inserm.fr.

Abstract

NK cell is an innate immune system lymphocyte lineage with natural cytotoxicity. Its optimal use in the clinic requires in vitro expansion and activation. Cytokines and encounter with target cells activate NK cells and induce proliferation, and this could depend on the presence of other immune cells. Here we activated PBMCs during 5 days with IL-2, with IL-2 plus the tumor cell line K562 and with the lymphoblastoid cell line R69 and perform integrated analyses of microRNA and mRNA expression profiles of purified NK cells. The samples cluster depending on the stimuli and not on the donor, indicating that the pattern of NK cell stimulation is acutely well conserved between individuals. Regulation of mRNA expression is tighter than that of miRNA expression. All stimuli induce a common preserved genetic remodeling. In addition, encounter with target cells mainly activates pathways related to metabolism. Different target cells induce different NK cell remodeling which affects cytokine response and cytotoxicity, supporting the notion that encounter with different target cells significantly changing the activation pattern. We validate our analysis by showing that activation down regulates miR-23a, which is a negative regulator of cathepsin C (CTSC) mRNA, a gene up regulated by all stimuli. The peptidase CTSC activates the granzymes, the main effector proteases involved in NK cell cytotoxicity. All-trans retinoic acid (ATRA), which induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity in an in vivo mouse model.

Copyright © 2014 Elsevier Ltd. All rights reserved.

KEYWORDS:

Cathepsin C; NK cells; Transcriptomics; miR-23a; miRNA

PMID:
24440757
[PubMed - in process]
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